”Lithium salt? You’re still using them?”
Bipolar disorder (BD) is a serious psychological disorder that increases the risk of suicide attempts and death by suicide and severely affects the social and occupational functioning of patients. 90% of patients experience a second episode of mindfulness after the initial recovery that led to the diagnosis, and therefore often require long-term mood stabilizer maintenance treatment.
Lithium has been a key drug in the preventive treatment of bipolar disorder for decades since Cade’s discovery of its therapeutic effects in 1949. Every psychiatrist has extensive experience with the use of lithium salts – including precautions for their use.
Over the past few decades, initially with aminomide, then valproic acid derivatives, then lamotrigine, and finally atypical antipsychotics; the choice of medications for maintenance treatment has grown, and the use of lithium has gradually declined; at least two factors have played an important role: concerns about adverse/toxic effects of lithium; and the fact that lithium is not good enough for prophylaxis in many patients.
Understanding Lithium Salts
The FDA approved lithium carbonate for the maintenance treatment of acute mania and BD. Lithium is recommended in the guidelines as the treatment of choice for BD. The effectiveness of lithium maintenance therapy is based on a placebo-controlled trial decades ago, as well as more recent studies using lithium as the active drug control group for new formulations. Recent findings support the long-term mind-stabilizing effects of lithium salts. However, the preventive effect of lithium salts on manic episodes is significantly better than the prevention of periodic depression. In addition, lithium salts reduce the risk of relapse in cyclic BD-II and BD-I.
Although lithium remains the drug of choice for maintenance treatment, it is not appropriate for every patient. The first step in any treatment, when considering lithium, should be to inform patients and their families of the risk-benefit of lithium therapy and other alternative options.
Evidence of efficacy
In terms of treatment benefits, the effectiveness of lithium for suicide prevention is outstanding. Most psychiatrists are familiar with the evidence for the efficacy of lithium in preventing suicide: long-term lithium treatment reduces the risk of suicide by as much as five times compared with placebo and other active treatments.The study by Cipriani and colleagues clarified this effect of lithium, but the study did not find a statistically significant difference in efficacy between lithium and other mood stabilizers (aminometrazine, lamotrigine, olanzapine). A systematic review by Yerevania and Choi found no drug or drug class comparable to the evidence for lithium salts in preventing suicidal behavior in patients with BD. Recent research evidence similarly supports the role of lithium salts in reducing morbidity and mortality in BD.
BD can be considered a neuroprogressive disorder, and there is the best evidence for the neuroprotective effects of lithium salts. The typical “cognitive retardation” effect of lithium has also been empirically verified, with the drug slightly impairing memory, information processing speed and creativity. However, this impairment does not continue to develop after 6 years of treatment and is not found in patients who respond well to lithium treatment. While some evidence suggests that the neuroprotective effects of lithium are only present in certain treatment responders, other studies have found that neuroprotection occurs independently. There is evidence to support the efficacy of lithium salts in basic neurocognitive impairment, but no evidence for the efficacy of valproic acid derivatives.
Grof defines an individual as an “optimal lithium responder” if the bipolar patient is protected from the disease by long-term prophylactic treatment with a single lithium salt. The continuing work of the international body of lithium research promises to further advance understanding of the genetic and other predictions of lithium treatment. Response or non-response to lithium treatment may identify an additional subgroup of patients with mood disorders – including some biphasic patients as well as monophasic patients – some with significant episodic, relapsing courses.
Safety considerations
1. Overdose
As patients begin to realize the benefits of long-term maintenance therapy with lithium, they are bound to become concerned about the associated adverse effects. We should weigh the risks and benefits of lithium against other alternatives: valproic acid derivatives and aminoglutethimide are associated with many potential systemic adverse effects; lamotrigine is arguably “only” a rash risk – but not effective in acute mania. Most atypical antipsychotics have a dual risk of metabolic syndrome and delayed-onset dyskinesia.
Recommended maintenance serum lithium concentrations are 0.5 or 0.6 to 0.8 mEq/L; some guidelines recommend 0.8 to 1.0 mEq/L for patients with prominent symptoms. most guidelines recommend close monitoring of lithium serum levels until mood normalizes, followed by testing every 3 to 6 months for the next 12 months and every 6 to 12 months thereafter. Further monitoring is required thereafter if factors that can alter serum lithium concentrations are introduced or if the patient experiences a relapse, or after a dose change.
The therapeutic index for lithium salts is relatively narrow. Clinicians need to be alert to the potentially serious risks and clinical manifestations of lithium salt toxicity. Serum concentrations need to be only 25% above the effective blood level on line (e.g., 1.2 mEq/L) to trigger clinical toxicity. The intensity and duration of high levels of lithium salt exposure can result in serious toxic effects. Clinical toxicity may occur at lower serum concentrations in elderly patients.
Excess serum lithium concentrations of 2 to 3 mEq/L can cause permanent residual nephrotoxicity and neurotoxicity in patients. Serum lithium concentrations above 4 mEq/L and/or the patient develops acute renal failure, CNS, or other severe clinical failure requiring dialysis. Lithium levels need to be monitored closely in situations that can increase lithium toxicity – especially in elderly patients – such as dehydration and drug interactions between NSAIDs or angiotensin – -converting enzyme inhibitors and thiazide diuretics.
2. Renal function
The well-known effects of lithium salts on renal function include: impairment of urinary concentrating capacity leading to irritable thirst, polyuria and nephrogenic uremia; and renal impairment nephropathy. Impaired urinary concentrating capacity is more common and has a rapid-onset and dose-dependent, in some cases transient, and more frequent occurrence in women. It induces inhibition of glycogen synthase kinase-3β by lithium, which interferes with the functionality of extracellular sodium channels and water channel protein-2 water transport channels, as well as antidiuretic hormone and aldosterone on cortical collecting duct principal cells. Low serum levels, single dose administration and, in more severe cases, co-administration of amiloride (an extracellular sodium channel potassium-preserving diuretic) may reduce the impairment of urinary concentrating capacity. Thiazide diuretics may be helpful, but require significantly lower lithium doses and close monitoring to avoid toxicity.
Some degree of nephropathy occurs in 20% of patients receiving long-term lithium therapy. It begins with kidney injury (creatinine levels above 1.5 mg/dL) and can progress to renal failure, which may require renal replacement therapy (dialysis or transplantation). The absolute risk of kidney injury, renal failure and/or renal replacement therapy with lithium is difficult to detect for practical reasons; however, recent studies have clarified the serious dangers of long-term lithium use. In a Meta-analysis of adverse effects of lithium therapy, McKnight and colleagues found that 0.5% of patients on long-term lithium therapy required renal replacement therapy, compared with 0.2% of the general population.
The results of the 2014 Swedish Renal Registry study showed a 1.2% incidence of lithium leading to renal replacement therapy. Patients with the worst treatment outcomes had been treated with lithium for more than 30 years, suggesting that close long-term monitoring and lowering the maintenance dose of lithium in recent years may have helped protect patients.Close and colleagues compared adverse effects of lithium or other mood stabilizers in bipolar patients after 1990. The researchers found significantly higher rates of kidney injury (10.2% vs. 3.1%) and kidney failure (2% vs. 0.7%) in patients treated with lithium.
Other findings suggest that the incidence of kidney disease may increase over time. The researchers found a rate of 0.14 (95%) per million population between 1992 and 1996.
CI, 0.06-0.22) cases of lithium leading to renal replacement therapy between 1992 and 1996, and 0.78 (95% CI, 0.67-0.90) cases per million population between 2007 and 2011. The rate of all patients treated with lithium resulting in renal replacement therapy increased from 0.2% to 0.7% during this period.
Three studies controlling for potentially confounding variables asserted a decisive role for lithium salts in this. Or because close studies underestimate the true duration of exposure, it is possible that nephropathy occurs after decades of sustained exposure. Poorer outcomes, such as nephropathy, may result when the hazard ratio (HR) is about 2.5; absolute risk differences are important: the number needed to treat harm (NNH: the number of cases in which a patient is treated with some control measure and one side effect needs to be treated) for renal replacement therapy is 330, and the NNH for renal failure is 660 in patients younger than 50 years of age and 44 in patients older than 50 years of age.
Physicians need to monitor patients with kidney disease for suggestive symptoms and estimated serum creatinine/glomerular filtration rate. Patients presenting with renal impairment need to undergo more in-depth evaluation; and physicians need to inform patients of alternative treatment options, such as the possibility of receiving low-dose single lithium salt therapy under close monitoring or the use of other mood stabilizers. Adjunctive lamotrigine, quetiapine, or compounded olanzapine-fluoxetine may be used in suboptimal lithium dose maintenance therapy for those at significant risk for periodic depression. Adjunctive bivalirudin, olanzapine, quetiapine, aripiprazole, or amiloride may be used in patients at significant risk of manic/mixed episode recurrence.
3. Thyroid function
Lithium salts more often affect thyroid function than other mood stabilizers. Lithium salts can affect the thyroid axis through a number of mechanisms. Studies have shown that hypothyroidism occurs in 30% of BD patients receiving lithium maintenance therapy and that 50% of these have an enlarged thyroid on ultrasound (compared to 20% of controls). Women are at greater risk of developing hypothyroidism.
In some cases, hypothyroidism or due to autoimmune thyroiditis, which is more common in patients with BD, is not associated with lithium salt exposure. Autoimmune thyroiditis may require further evaluation and treatment, and hypothyroidism is not a contraindication to lithium treatment. Psychiatrists may manage the condition by supplementing patients with levothyroxine.
Thyroid stimulating hormone testing is recommended every 3 months for the first 6 to 12 months; thereafter, testing every 6 to 12 months is recommended (frequency may be increased for women over 45 years of age). A key teaching point for residents is to be aware of hypothyroidism in patients with BD on continuous lithium therapy and in patients with rapidly progressing depression; hypothyroidism is a typical cause of secondary depression. In addition, lithium-induced hypothyroidism can lead to mania.
4. Hypercalcemia and hyperparathyroidism
Lithium salts cause hypercalcemia and hyperparathyroidism due to their direct effect on parathyroid calcium sensitivity. In one study, 8.6% of BD patients treated with lithium were found to have hyperparathyroidism. The new guidelines recommend periodic monitoring of calcium levels (rather than conventional parathyroid hormone) at baseline and during late treatment. Patients should also be informed of adverse effects including the possibility of parathyroid adenoma, which may require surgical removal. However, the prognosis for surgery for these benign tumors is better.
5. Brugada Syndrome
Brugada syndrome is described by the FDA as a congenital arrhythmia characterized by ST-segment elevation in the precordial leads, and ventricular arrhythmias can lead to syncope or risk of sudden death. Because lithium prompts Brugada syndrome even at therapeutic blood concentrations, it is used as a contraindication to lithium therapy. It may be induced by sodium channel blockade, so other psychotropic drugs may also carry this risk. Physicians should warn patients of this risk and advise them to discontinue lithium use and seek immediate medical attention if unexplained syncope occurs. Lithium can affect both atrial and ventricular conduction and requires special attention when used in combination with other cardiac conduction effect drugs or in overdose.
6. Other safety precautions
The FDA has classified the safety of lithium salts as Class D in women during pregnancy because of the association of early trimester exposure with subtricuspid valve malformation (Ebstein malformation) and other cardiovascular malformations. In recent teratogenic studies, the risk of fetal cardiovascular defects from first-trimester lithium exposure was 4% compared with 0.6% in controls without teratogenic exposure. The incidence of pregnancy complications in women who used lithium salts during pregnancy exceeded 20%. Lithium salts can also pose a risk to the infant through the nursing mother because of their high concentration in breast milk.
Another caveat to lithium use is the risk of discontinuation. A 20-year follow-up of 346 bipolar patients found that the index of affective morbidity was consistently stable, consistent with the long-term outcome of patients on continuous medication. On the other hand, patients had a significantly higher risk of cyclic relapse compared to patients who continued lithium, even after stable remission and tapering off the medication. Interruptions in medication use also increase the risk of suicide in patients. The risk of relapse and suicide was significantly higher in patients with abrupt discontinuation than in those with gradual discontinuation. Moreover, the disease may become refractory after discontinuation in some patients.
Conclusion
In conclusion, lithium salts have an important role in reducing morbidity and mortality in patients with BD. Psychiatrists can optimize the benefit of lithium therapy by carefully selecting patients for long-term treatment, educating patients about the full risk-benefit profile, regularly monitoring for adverse effects and serum lithium concentrations, and keeping treatment at the lowest possible dose maintenance.
Physicians should offer prophylactic lithium therapy to patients whose longitudinal disease pattern meets Grof’s “best treatment responder” profile, unless the patient has a medical contraindication or has poor follow-up reliability. However, this does not mean that patients with other conditions cannot be treated with lithium maintenance therapy. Even patients without “best responder” characteristics may still have a cumulative benefit, and at some point most patients with BD (or patients with periodic monophasic depression) should be informed of this.
One approach is to combine the most appropriate dose of lithium (to reduce short-term and possibly long-term adverse effects) with other mood stabilizers to ensure symptom/episode control in patients who do not do well on lithium alone. This approach was derived from the Lithium Treatment Moderate-Dose Use Study. In the first outcome report, lithium combined with optimized individualized treatment at month six did not show a significant advantage, but patients in the lithium treatment group (mean serum concentration 0.4 to 0.47 mEq/L) received 23% less atypical antipsychotics.
It may take longer to see whether moderate doses of adjunctive lithium treatment have suicide-preventative effects and neuroprotective benefits, let alone neuroprotective effects. Further data from this work, as well as from the international body of lithium research, will help us to continue to optimize lithium use.
So perhaps my answer to the question, “Should we continue to use lithium?” is that the answer may still be “yes” in the future.